12-93678877-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003805.5(CRADD):c.103A>G(p.Ile35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,614,182 control chromosomes in the GnomAD database, including 693 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (60 hom., cov: 32)
  • Exomes 𝑓: 0.026 (633 hom.)
• Consequence: CRADD NM_003805.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.00

Genes affected

CRADD (HGNC:2340): (CASP2 and RIPK1 domain containing adaptor with death domain) This gene encodes a protein containing a death domain (DD) motif. This protein recruits caspase 2/ICH1 to the cell death signal transduction complex, which includes tumor necrosis factor receptor 1 (TNFR1A) and RIPK1/RIP kinase, and acts in promoting apoptosis. A mutation in this gene was associated with cognitive disability. A related pseudogene is found on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023779273).
• BP6: Variant 12-93678877-A-G is Benign according to our data. Variant chr12-93678877-A-G is described in ClinVar as [Benign]. Clinvar id is 1245343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0209 (3187/152306) while in subpopulation NFE AF= 0.0275 (1870/68026). AF 95% confidence interval is 0.0265. There are 60 homozygotes in gnomad4. There are 1632 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRADD	NM_003805.5	c.103A>G	p.Ile35Val	missense_variant	2/3	ENST00000332896.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRADD	ENST00000332896.8	c.103A>G	p.Ile35Val	missense_variant	2/3	1	NM_003805.5	P1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3189 AN: 152188 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0228 AC: 5725 AN: 251460 Hom.: 123 AF XY: 0.0224 AC XY: 3043 AN XY: 135916

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.00942

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00941

Gnomad FIN exome AF: 0.0706

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0264 AC: 38526 AN: 1461876 Hom.: 633 Cov.: 31 AF XY: 0.0256 AC XY: 18653 AN XY: 727238

Gnomad4 AFR exome AF: 0.00382

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.00934

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00947

Gnomad4 FIN exome AF: 0.0692

Gnomad4 NFE exome AF: 0.0286

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0209 AC: 3187 AN: 152306 Hom.: 60 Cov.: 32 AF XY: 0.0219 AC XY: 1632 AN XY: 74476

Gnomad4 AFR AF: 0.00508

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.0701

Gnomad4 NFE AF: 0.0275

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0236 Hom.: 69

Bravo AF: 0.0170

TwinsUK AF: 0.0310 AC: 115

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0284 AC: 244

ExAC AF: 0.0228 AC: 2769

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0250

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	13
Dann	Benign	0.94
DEOGEN2	Benign	0.060	T;T;.;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.66	T;.;T;T;T
MetaRNN	Benign	0.0024	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.62	N;N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.0010, 0.0050	.;B;.;B;B
Vest4		0.040
MPC		0.088
ClinPred		0.0036	T
GERP RS		1.7
Varity_R		0.034
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs52807869; hg19: chr12-94072653;